A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected … · 2019. 10. 10. ·...

10.1161/CIRCULATIONAHA.119.042891

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A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected Acute

Coronary Syndromes: The Rapid Assessment of Possible ACS

In the Emergency Department with High Sensitivity Troponin T

(RAPID-TnT) Study

Running Title: Chew et al.; RAPID-TnT

Derek P. Chew, MBBS, MPH, PhD1,2,3; Kristina Lambrakis, BSc3;

Andrew Blyth, MBChB, PhD1,3; Anil Seshadri, MBBS1,3; Michael J.R. Edmonds, MBBS3;

Tom Briffa, PhD5; Louise A. Cullen, MBBS, PhD6,7,8; Stephen Quinn, PhD9;

Jonathan Karnon, PhD1; Anthony Chuang, MBBS1,3; Adam J. Nelson, MBBS2,4;

Deborah Wright, MNSc3; Matthew Horsfall, RN3; Erin Morton, PhD1;

John K. French, MBChB, PhD10; Cynthia Papendick, MBBS3

1College of Medicine & Public Health, Flinders University of South Australia, Adelaide,

Australia; 2South Australian Health and Medical Research Institute, Adelaide, Australia;

3South Australian Department of Health, Adelaide, Australia; 4School of Medicine,

University of Adelaide, Adelaide, Australia; 5School of Population and Global Health,

University of Western Australia, Perth, Australia; 6Dept. of Emergency Medicine, Royal

Brisbane and Women’s Hospital, Brisbane, Australia; 7School of Public Health,

Queensland University of Technology, Brisbane, Australia; 8School of Medicine,

University of Queensland, Brisbane, Australia; 9Department of Statistics, Data Science

and Epidemiology, Swinburne University of Technology, Melbourne, Australia;

10Department of Cardiology, Liverpool Hospital, University of New South Wales,

Sydney Australia

Address for Correspondence:

Derek P. Chew MBBS MPH PhD

Flinders University

Flinders Drive, Bedford Park South

Australia, 5042, Australia Tel:+618

8404 2001

Fax:+618 8404 2150 Email: [email protected]

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Abstract

Background: High-sensitivity troponin assays promise earlier discrimination of myocardial

infarction (MI). Yet, the benefits and harms of this improved discriminatory performance when

incorporated within rapid testing protocols, with respect to subsequent testing and clinical events,

has not been evaluated in an in-practice patient-level randomized study. This multi-center study

evaluated the non-inferiority of a 0/1-hour high-sensitivity troponin T (hs-cTnT) protocol

compared with a 0/3-hour masked hs-cTnT protocol in suspected ACS patients presenting to the

emergency department (ED).

Methods: Patients were randomized to either 0/1-hour hs-cTnT (reported to the limit of

detection [


3

CI = Confidence Interval

COPD = Chronic obstructive pulmonary disease

CPR = Cardiopulmonary resuscitation

CT = Computer tomography

cTnT = Cardiac troponin T

DSMB = Data safety and monitoring board

ECG = Electrocardiogram

ED = Emergency department

EST- Exercise stress test

HF = Heart failure

HR = Heart rate

Hs-TnT = High-sensitivity cardiac troponin T

IQR = Interquartile range

IRR = Incidence rate ratio

LBBB = Left bundle branch block

LOS = Length of stay

MI = Myocardial Infarction

ng/L = Nanograms per litre

Non-STEACS = non-ST segment elevation acute coronary syndrome

PCI = Percutaneous coronary intervention

STEMI = ST elevation myocardial infarction

T4MI = Type 4 myocardial infarction

T5MI = Type 5 myocardial infarction

TWI = T wave inversion

URL = Upper reference limit

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Clinical Perspective

What is new?

• High-sensitivity troponin assays have promised improved diagnosis myocardial infarction

enabling more timely decision-making in the emergency department.

• Resetting clinical practice to a higher level of troponin sensitivity and more rapid testing

sequence may also lead to unanticipated effects, such as increased procedure-related

myocardial injury and infarction.

• This patient-level prospective randomized comparison of a 0/1-hour protocol using hs-

cTnT embedded within routine practice confirmed a low rate of 30-day death or MI for

patients receiving a rule-out MI recommendation, but did not lead to a reduction in these

events overall.

What are the clinical implications?

• This study supports the routine implementation of a 0/1-hour high-sensitivity troponin T

protocol for the early rule-out of patients with suspected ACS.

• However, use of invasive coronary investigation is increased among patients with newly

identified low-concerntration troponin elevations and strategies to mitigate associated

cardiac injury may require further refinements in acute coronary syndrome care.

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Introduction

The introduction of high-sensitivity troponin assays, which enables detection of very low levels

of myocardial injury, have promised to enhance clinical practice and improve outcomes through

earlier detection of myocardial infarction (MI).1,2 Yet, to date, prospective randomized

evaluations of high-sensitivity troponin testing has not demonstrated reduction in subsequent

ischaemic events.3,4 Given greater sensitivity translates to improved negative predictive value,

these assays may allow for the exclusion of significant cardiac events more rapidly and with

greater certainty, enabling earlier discharge from emergency services. Such protocols for rapid

triage of patients with suspected acute coronary syndromes (ACS) have been developed and

incorporated into clinical guidelines.5-9 While use of high sensitivity troponin assays in Europe is

more common (>60%), uptake in North America and the Asia Pacific region is estimated to be

much lower (~ 20% and ~30% respectively) and of these centres, very few employ a 0/1-hour

rapid triage protocol.

However, studies supporting these protocols have yet to include contemporaneously

enrolled comparative patients managed without access to the improved precision of high

sensitivity troponin and are subject to changes in decision-making and clinical care that may not

be due to the deployment of the high sensitivity troponin assay. Furthermore, although these

guidelines focus on the exclusion of MI, concerns remain regarding the implications of increased

testing and coronary revascularization among those patients with low levels of myocardial

injury.10-13 Resetting clinical practice to a higher level of troponin sensitivity and more rapid

testing sequence may lead to unanticipated effects, such as increased procedure-related

myocardial injury and infarction. Hence, comparative randomized evaluation of a 0/1-hour

protocol that relies on the diagnostic performance of high-sensitivity troponin assays, compared

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with and embedded within existing practice, where the improved diagnostic precision of these

assays has not been utilized, is required to evaluate the actual value of this innovation on clinical

decision-making, downstream cardiac testing and the balance of benefits and harms associated

with any change in practice.14 Therefore, we conducted an “in practice” prospective randomized

multicenter clinical trial embedded in ED assessment of suspected ACS and investigating an

accelerated 0/1-hour decision-rule based on high sensitivity troponin T (hs-cTnT) compared with

a 0/3-hour protocol, in which the troponin T assay’s high-sensitivity performance characteristics

were masked.

Methods

Study Design and Funding

The design of the Rapid Assessment of Possible ACS In the emergency Department with high

sensitivity Troponin T (RAPID-TnT) trial was a prospective patient-level randomized non-

inferiority evaluation of a 0/1-hour protocol using a hs-cTnT reporting format compared with a

0/3-hour protocol with troponin T results masked below 29 ng/L, in participants with suspected

ACS, with respect to death or MI by 30 days. Secondarily, this study sought to confirm that

participants discharged from the ED following assessment for suspected ACS in accordance with

a 0/1-hour hs-cTnT protocol have a death or MI incidence rate by 30 days of


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Registry Registration Number ACTRN12615001379505). The study was investigator-initiated

and funded by the National Health and Medical Research Council of Australia (APP1124471)

with supplementary support provided via unrestricted grant from Roche Diagnostics

International (Rotkreuz, Switzerland). Funding was secured after enrollment had commenced,

and was not contingent on access to study data or protocol modification. Data supporting the

findings of this study are available from the corresponding author upon reasonable request.

System-level Masking of Troponin T reporting enabling Study Implementation

In April 2011, the Roche Diagnostics (Cobas) Elecsys 5th generation hs-TnT assay (LoD: 5ng/L,

99th percentile: 14ng/L) was implemented as the sole troponin assay available within all public

hospital EDs in South Australia via a single pathology provider. Due to uncertainty regarding the

balance between the potential increase in downstream cardiac testing versus the possible benefits

of increased MI diagnosis with implementing an upper reference limit of 14ng/L, the decision

was made at adoption to numerically align the lower clinical reporting limit of the 5th generation

assay to that of the previous assay (i.e. masked, with the lower reference limit reported as

“≤29ng/L” rather than to report down to the LoD [5ng/L]). The decision was made with the

recognition that the 5th generation hs-cTnT assay had greater sensitivity compared with the same

concentrations reported on the 4th generation assay. Specifically, in maintaining reported lower

reference limit at ≤29ng/L while transitioning fromform the 4th generation to the 5th generation

assay, this reduced the actual lower reference limit reported to clinicians, since a concentration of

29ng/L using the 4th generation assay equates to a concentration of ~43ng/L on the 5th generation

assay. 17 The clinical implications of access to troponin concentrations between 5-29 ng/L to

enable diagnostic classification consistent with international standards was then prospectively

evaluated in a prior randomized trial (n=1937) showing modest differences in treatment and no

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difference 12-month rates of death or recurrent acute coronary syndromes.3 Hence, this masked

reporting policy was maintained enabling a patient-level implementation of the current

randomized trial. Uniquely, apart from the preliminary trial, participating EDs had therefore

remained masked to troponin T concentrations below 29ng/L; thus clinicians had no prior

clinical experience with hs-cTnT results below 29ng/L, nor the 0/1-hour protocol. This

controlled access to troponin results enabled a randomized evaluation to be embedded within

routine practice. In this setting, absolute troponin T values were reported only for participants

randomized to the 0/1-hour arm and the interpretation was guided by the study protocol (see

below). Maintenance of the integrity of the two randomized reporting formats was managed

through the single statewide pathology reporting system. After capture of baseline data,

randomization in permuted blocks of four occurred independently at each hospital was

implemented by a combined envelope and web-based randomization process at study initiation.

Study Population

This study focused on patients in whom initial clinical and ECG assessment did not provide a

high diagnostic likelihood for MI, as the safety of early discharge is less clinically relevant in

this cohort. Similarly, reliant on physician judgement at initial assessment, the study sought to

include participants for whom care may be influenced by rapid triage protocols (i.e. eligible for

early ED discharge). Therefore, participants presenting to the ED were included if there was the

intention to undertake troponin testing and they had: clinical features of chest pain or suspected

ACS as the principal cause for investigation; baseline electrocardiogram (ECG) interpreted as

not definitive for coronary ischemia; were ≥18 years of age; and willing to give written consent.

Participants were excluded if they presented for chest pain not suspected to be from a cardiac

cause; presented as a result of a transfer from another hospital; presented for suspected ACS

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within 30 days of last presentation; required permanent dialysis; or were unable to complete the

clinical history questionnaire due to language or comorbidity.

Study Protocol

To maintain integrity of the troponin testing procedure, all participants were consented and

randomized after senior ED physician interpretation of initial ECG, but before troponin results

were available. For participants randomized to the 0/1-hour hs-cTnT arm, ED management

pathways for each of “rule-in”, “observe” and “rule out” were based on previous studies and

were formalized in a protocol.6,18 Specifically: “rule-out” with discharge to primary care with

instructions regarding recurrent chest pain and primary prevention advice was recommended

when the baseline troponin was


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≤29ng/L was discharge from ED, with subsequent outpatient functional testing based on age >65

years and/or the presence of three or more cardiac risk factors. All participants were referred

back to their primary care physicians for further evaluation. Clinical information required for

calculation of various risk scores (i.e. the Emergency Department Assessment of Chest Pain

Score [EDACS], History ECG Age Risk factors and Troponin [HEART] Score, Global Registry

for Acute Coronary Events [GRACE] score and Thrombolysis In Myocardial Infarction [TIMI]

score for non-STEACS was collected and available to clinicians but use was not mandated.19-22

Education on protocol interpretation was provided at the outset and throughout study

implementation. Study coordinators were comprehensively trained and were present during the

initial assessment of each patient regardless of study arm to assist in data collection and to

facilitate knowledge of the protocol recommendations. Clinicians were also informed of the

previously published positive and negative predictive values for rule-in MI (72%) and rule-out

MI (99%) triage recommendations.6 While these protocols provided recommendations, clinicians

retained discretion to vary management, in order to provide inpatient or outpatient care that they

deemed most appropriate for the patient.

Data Collection and Outcome Measures

ED discharge was defined as those patients not admitted to inpatient wards or extended care

facilities within the ED. Participant records were reviewed for hospital actions including

subsequent cardiac testing (e.g. stress testing [ECG, Echocardiography, Nuclear, CMR],

echocardiography, CT coronary angiography (CTCA) and invasive coronary angiography and

coronary revascularization), ED length of stay (LOS), total acute care LOS, and outpatient health

care attendances for up to 30 days. To enhance capture of all clinical episodes, systematised

interrogation of embedded data linkage methods for pathology, clinical and patient information

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enabled the assessment of representation to emergency services and late troponin results, as well

as re-admissions and subsequent coronary revascularization procedures across the state.

The primary measure of the 0/1-hour hs-cTnT protocol was the incidence of composite all-cause

mortality or new MI occurring within 30 days of randomization using the fourth universal

definition.16,23 Of note, MI diagnosed within 12 hours of randomization among participants

continuously in-hospital was considered as the index presenting MI and not included as an

endpoint event. 16,23 An MI documented to have commenced outside this time (recurrent MI), or

within 12 hours of randomization among participants already discharged from hospital (missed

MI) were considered an endpoint event. The timing and subclassification of all suspected MIs

were adjudicated by a clinical events committee (CEC) consisting of 4 independent cardiologists.

Each event was discussed at CEC meetings and disagreements settled by majority. CEC

adjudicators were provided unmasked troponin concentrations (i.e. down to the LoD of 5ng/L)

for events in both study arms (i.e. 0/1-hour hs-cTnT and standard masked hs-cTnT arms). This

enabled adjudication of MI events to the 4th universal definition of MI and allowed adjudication

of acute and chronic myocardial injury. For adjudication of acute injury, events required

documentation of a rise and/or fall in troponin T (defined as a change >20% with a rate of

change of ≥3ng/L/hr) with at least one sample above 14ng/L.24 Subsequent sub-classification

into MI type 1, type 2, type 4a and type 5 required clear evidence of ischaemia by a typical

clinical history (type 1 and 2 only) or ischaemic ECG changes (except for type 5), new

pathological Q waves, new wall motion abnormalities on cardiac imaging, or angiographic

findings. As per the 4th universal definition, type 4a and type 5 MIs were not diagnosed if

troponin concentrations were not documented to either be normal, stable or falling prior to the

procedure. Furthermore, type 2 MI required evidence supply-demand ischaemia.23 Re-

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presentation to hospital or late troponin elevations with a rise and/or fall pattern without

verifiable evidence of coronary ischaemia were reported as acute injury, whilst hospital

presentations with troponin elevations >14ng/L not meeting the rise and/or fall criteria were

reported as chronic injury. Key secondary endpoints included: components of the primary

endpoint; representation for chest pain, readmission for unstable angina (defined as chest

pain/discomfort with an exacerbating pattern or occurring at rest, associated with dynamic ECG

changes consistent with ischemia, or functional testing consistent with ischemia, and/or

demonstrated coronary stenosis>70% by visual estimation); rehospitalization for non-elective

coronary revascularization, peripheral artery disease, cerebrovascular accidents; congestive

cardiac failure without MI, atrial and ventricular arrhythmias; and bleeding events classified

under the Bleeding Academic Research Consortium BARC criteria, as well as TIMI major or

minor and GUSTO major and minor bleeding criteria; as documented by hospital records within

30 days of randomization.25

Statistical analysis

The study sample size focused on observing sufficient patients with a rule-out MI

recommendation and was informed by a previous randomized trial of unguided hs-cTnT

reporting. 3 The event rate among those discharged directly from ED within the hs-cTnT arm of

that published study was 0.3% [1/368] while in a comparable observational trial of 0/1-hour

reporting it was 0.1%.3,6 Consequently, a primary endpoint rate of 0.3% in the rule-out MI in the

0/1-hour arm (discharge recommendation) was assumed, and it was estimated that 1212 rule-out

MI participants eligible for discharge would need to be observed to evaluate that the event rate in

the 0/1-hour was below a “clinically acceptable” 1% absolute rate. 15 However, since

randomization occurred before troponin T concentrations were available, the sample size was

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increased to allow for 25% of participants enrolled with a presumed low to moderate diagnostic

likelihood of MI, to then have a ‘positive’ troponin T concentration of >29ng/L. For comparison

of care and care-associated outcome between the two study protocols, a non-inferiority margin

for the comparison of all randomized patients was arbitrarily set at 0.5%, reflecting a clinical

judgement that treatment under the 0/1-hour protocol was no worse than 0.5% greater than

standard care (number needed to harm (NNH) of 200). Review by the data safety monitoring

board in April 2019 suggested that equipoise for the performance of the “rule-out MI”

recommendation was no longer present, thus the decision was made to end enrollment.

Participant flow through this study is reported in the CONSORT diagram (Figure 1). The

primary analysis employed the intention-to-treat (ITT) population including all randomized

participants. The primary analysis assessed the non-inferiority of the 0/1-hour arm, defined as

incidence of all-cause death or MI within 30 days of randomization in the standard arm plus

0.5%, using poisson regression with robust standard errors. This is reported as an incident rate

ratio (IRR and 95% CI). Tests for superiority were undertaken only if non-inferiority was met.

The key secondary analysis determined if the incidence rate among the participants discharged

under the 0/1-hour hs-cTnT protocol was not inferior to the accepted ED standard of 1.0% and

was conducted by examining whether the 97.5% upper confidence bound crossed this value.

Further, sensitivity analyses were undertaken evaluating the per-protocol population for safety of

the rule-out protocol. (Supplemental Methods) Exploratory sub-analyses were confined to

participants with an initial (first 2) troponin ≤29ng/L, i.e. in the range where troponin reporting

format (e.g. actual concentration 5-29ng/L versus ≤29ng/L) differs between the two study arms.

Given concerns regarding the risk of periprocedural myocardial injury or infarction, these

analyses are reported without adjustment for multiple testing. Aspects of subsequent care are

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reported as percentages and odds ratios (95% CI), and the interaction between the initial level of

hs-cTnT (stratified as


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24% of patients in the standard arm received a troponin test > 4 hours after initial assessment.

Among participants presenting with at least one troponin T concentration >14ng/L during the

index presentation, the observed frequencies of the following were: MI type 1 - 124/3288 (4%),

MI Type 2 - 39/3288 (1%), acute injury – 58/3288 (2%), and chronic injury - 479/3288 (15%).

These proportions did not differ between study arms. Among participants randomized to the 0/1-

hour hs-cTnT protocol, 136/1646 (8%), 308/1646 (19%) and 1187/1646 (72%) were considered

“rule-in MI”, “observe” and “rule-out MI” respectively, while 15/1646 (1%) had insufficient

information for a triage recommendation. (Supplemental Table 2) The sensitivity and specificity

of a rule in recommendation for MI diagnosed within the index presentation was 88.1% and

94.7%, respectively, with a positive predictive value of 38.2% (95% C.I.: 30-47%). The positive

likelihood ratio for index MI was 16.5 (95% C.I.:13.1-20.7) with the rule-in recommendation.

Subsequent care

The 0/1-hour arm was associated with a higher rate of direct discharge from the ED (0/1-hour

arm: 748/1646 (45%) versus standard arm: 545/1642 (33%), Odds Ratio 1.68: 95% CI 1.45-1.93,

p


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3.4-6.4) hours versus 5.6 (IQR: 4.0-7.1) hours, p=0.001).(Supplemental Figure 1) The median

LOS in acute care was lower in the 0/1-hour arm compared with the standard masked hs-cTnT

arm (0/1-hour arm: 5.3 (IQR: 3.7-23.4) hours versus standard arm: 6.4 (IQR: 4.9-23.1) hours,

p


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increase in acute injury, Type 4a and Type 5 MIs among the participants randomized to the 0/1-

hour hs-cTnT protocol (0/1-hour arm 26/1646 (1.6%) versus standard arm 17/1642 (1.0%), IRR:

1.53 (95% C.I. 1.15-2.04), p=0.004), (Supplemental Figure 3) with other outcomes similar

between groups. Among all participants receiving a rule-out MI triage recommendation, the

primary endpoint was observed in 5/1187 (0.4%), and among those participants discharged

directly from the ED with a rule-out MI recommendation, 2/630 (0.3% [95% C.I. 0.02-0.06])

experienced the primary endpoint. Comparable rates of 30-day death or MI were observed

among those directly discharged from the ED in the standard arm (2/495 [0.4, 95% C.I. 0.01-

0.08]). The negative predictive value of the rule-out MI recommendation of the 0/1-hour hs-

cTnT protocol for 30-day death or MI was 99.6% (95% C.I. 99.0-99.9%, specificity 73.2%).

Rates of the primary outcome and key secondary outcomes by triage categories are provided in

table 4.

Discussion

This in-practice patient-level randomized comparison of a 0/1-hour hs-cTnT protocol , observed

similar overall clinical outcomes compared with clinical management based reporting practices

that did not employ the full enhanced diagnostic performance of the hs-cTnT assay. This study

confirmed an acceptable safety profile for early discharge based on a rule-out MI profile.

However, while resetting the sensitivity of troponin assays to a greater level of precision has

improved the negative predictive value of troponin testing, the potential for precipitating

myocardial injury-associated increases in coronary angiography and revascularization for those

patients not receiving a rule-out MI recommendation was also observed.

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Previous prospective observational studies have suggested patients with very low

troponin concentrations and a small change over 1 hour have a < 1% risk of subsequent 30 day

events.18,26 We confirmed in a randomized trial that patients prospectively managed under this

recommendation experienced a risk tolerance of death or MI by 30 days that has been commonly

considered acceptable.15 Nevertheless, while discharge from the ED occurred sooner and

morefrequently, with clear implications for reducing ED congestion, clinical adoption of early

discharge was cautious with many patients receiving a rule-out MI recommendation still

undergoing extended observation. The rates of admission and ED LOS in this study are higher

than other prospective observational studies where systems of practice have been given time to

become established. The rates of subsequent events among those discharged under rule-out

recommendation was slightly higher. 27 These observations are likely the consequence of the

parallel randomized pragmatic design embedded within existing practices leading to reduced

clinical uptake of the protocol recommendations.27,28This finding highlights the need for clinical

practice to evolve in response to innovations, and suggests that even greater gains in assessment

efficiency may be possible if clinical adoption of the 0/1-hour protocol is systematized as routine

practice. Within our system of care, this group appeared to have lower rates of subsequent

functional stress testing, as has been observed by others, suggesting higher clinical confidence in

excluding ACS with hs-cTnT testing alone.29 However, the modestly higher rates of repeat ED

presentations for investigation of chest pain with the 0/1-hour hs-cTnT protocol may reflect

patient expectations for subsequent cardiac testing. 30 The incremental value of testing for “flow-

limiting” CAD very early after hs-cTnT has ruled out MI requires further clarification.31,32 Our

findings appear to support the routine implementation of the 0/1-hour decision protocol in

clinical practice to reduce ED congestion.

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This study focused on the use of a rapid hs-cTnT decision-tool to rule out MI among

patients with suspected ACS, which is arguably where the greatest benefits of high-sensitivity

troponin assays reside. Specifically, this study excluded patients with initial ECG changes highly

suggestive of coronary ischaemia, or those with concurrent clinical conditions that required more

protracted assessment that made consideration of early discharge irrelevant. As a consequence,

the rate of index MI was lower than documented in other observational studies where only

patients with ST-segment elevation on the initial ECG were excluded.27,28 Despite the low index

MI rate, representation to the ED occurred in over 13% of the population within 30 days and was

associated with a high proportion of repeat troponin testing (~50%). As seen by others, more

than 6% of these participants had at least one troponin T concentration above 14ng/L

reported.4,33 These observations suggest better strategies are needed for the investigation and

management of the considerable number of patients who are classified as “observe” or “rule-in

MI”. Notably, when implementing the Fourth Universal Definition of MI, nearly half of all these

acute injury profiles observed occurred following coronary revascularization procedures, and of

these, half had clear corroborating evidence of ischaemia to establish the diagnoses of Type 4a

and Type 5 MI, thereby highlighting the recognized risks associated with an early invasive

strategy for the management of ACS. 23 Within this context, greater sensitivity for ruling-in

patients was associated with greater use of invasive coronary angiography and subsequent

revascularization in the subgroup of patients with an initial troponin concentration 29ng/L,

where the diagnostic information differed between study arms, as observed in other studies.34,35

In this study, an increase in revascularization among the subgroup with an initial troponin

concentration 29ng/L was also observed. While exploratory, a slightly higher rate of peri-

procedural MIs and acute injury troponin profiles was evident. No reduction in the rates of 30-

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day Type 1 MI was documented. This observation has not been well reported within non-

randomized evaluations of high-sensitivity troponin protocols without directly comparative

populations and systematized troponin collection. 27 Although our data supports the routine

implementation of hs-cTnT to facilitate safe early ED discharge, the enhanced detection of

myocardial injury has implications for therapeutic decision-making. Current strategies for the

management of ACS have established their balance of risk and benefit in a prior era of troponin

when test performance was substantially inferior to currently available tests.36 Potentially,

extension of the management strategies for ACS to those with low-modest troponin elevations

using high-sensitivity troponin assays may not be associated with the same favourable profile of

risk and benefit as seen in earlier ACS studies. Effective translation of the improved

discriminatory capacity of high-sensitivity troponin into better outcomes for patients may require

refinements in treatment approaches for these lower risk patients.37 Further insights into the risks

and benefits of increased rates of coronary revascularization will be provided by the 12-month

outcomes of this study.16

Nevertheless, the state-wide control of troponin reporting not only masked the high

sensitivity troponin results ≤29ng/L for all patients receiving emergency care prior to this RCT,

but it also ensured that clinicians had little to no experience in interpreting hs-cTnT results

allowing de novo evaluation of the impact of the new testing information on subsequent care.

Our approach of embedding the study within a single health system jurisdiction’s clinical data

environment allowed the routine collection of all subsequent care and outcome. Moreover, it

enabled the conduct of patient-level “randomization in practice” to provide a comparative

evaluation of hs-cTnT that is necessary to fully understand the balance of benefits and any

unintended consequences from the resultant changes in therapeutic decision-making.

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Some limitations should be considered. Within the standard arm, troponin concentrations

below 29ng/L were masked and therefore clinicians were prevented from applying the current

universal definition of MI which calls for MI/injury diagnosis to be applied, as opposed to

unstable angina, when the troponin concentration exceeds 14ng/L with a rise and/or fall pattern.

However, our previous prospective randomized comparison comparing unmasked and masked

results showed no difference in death or recurrent ACS when levels below 29 ng/L were made

available. Similarly, in this study there are no differences in index MI rates between the study

arms, suggesting that any clinical impact associated with differing troponin concentration

thresholds for diagnosing MI versus unstable angina is likely to be modest. Further, the standard

arm also differs slightly from the published 0/3-hour protocol using a conventional assay given

the use of the masked hs-cTnT assay and the absence of formal risk scoring. However, the low

event rates among patients discharged in the standard arm of this study attests to the safety of

this practice. The proportion of patients presenting with index MI was lower than anticipated,

although the rate of recurrent presentations with associated elevated troponin T concentrations

>14ng/L was higher than expected. Not only does this likely reflect more liberal troponin testing

practices, but also highlights the potential for an increase in the frequency of clinical

presentations associated with a “positive” test. Yet, observational data suggests that

generalization of the 0/1-hour protocol’s rule-out MI performance to practices with higher

thresholds for troponin testing (i.e. higher pretest probabilities for MI) should yield similar

results. 18 Furthermore, early discontinuation of the study based on the acceptable event rate

among those discharged with a rule-out MI recommendation may have prevented assessment of

whether a 0/1-hour hs-cTnT protocol improves 30-day clinical outcomes. However, superiority

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for the shortened protocol is not expected given the higher event rates observed in this arm, and

the true test of benefit will depend on the planned 12-month evaluation outcomes .

In conclusion, implementation of a 0/1-hour hs-cTnT protocol for the triage of suspected

ACS patients enabled more rapid decision-making to discharge low risk patients with suspected

ACS. Improving short term clinical outcomes among patients’ newly recognized troponin T

elevation with a hs-cTnT assay will require evolution in the management strategies for these

more frequently encountered patients.

Contributions

Study design and protocol development: DPC, TB, LAC, SQ, JK, CP

Sourced funding from NHMRC Australia DPC, TB, LAC, SQ, JK

Sourced funding Roche Diagnostics: DPC, CP

Study Steering Committee and Implementation: DPC, KL, AB, AS, MJRE, TB, LAC, SQ, JK,

AC, AJN, DW, MH, EM, JKF, CP

Randomization: SQ

Analysis: DPC, SQ, JK

First Drafting of Manuscript: DPC, TB, LAC, SQ, JK, JKF, CP

Final Approval of Manuscript: DPC, KL, AB, AS, MJRE, TB, LAC, SQ, JK, AC, AJN, DW,

MH, EM, JKF, CP

Data Safety Monitoring Board: Stephen J. Nicholls (Chair), Philip G. Aylward, Matthew

Worthley, Richard Woodman (statistician)

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Clinical Events Committee: John K French (Chair), Sheraz Nazir (cardiologist), Dylan Jones

(cardiologist), Amera Halabi (cardiologist), Nikhil Pal (cardiologist),

Acknowledgments

The team would like to acknowledge the support and collaboration form Dr Penny Coates and

team from SA Pathology in their role maintaining the statewide troponin reporting policy and

facilitating access to the troponin results required for the implementation of the study.

Sources of Funding

Support for this study was granted from National Health and Medical Research Council of

Australia (APP1124471) and Roche Diagnostics (Basel, Switzerland). Neither funder has

requested any modification of the protocol not access to the data on completion.

Disclosures

The authors are solely responsible for the design and conduct of this study including study

analyses, the drafting and editing of the paper and its final contents. Funding was sought after

the study was designed, approved by the human research ethics committee, and initiated.

DPC: Speaker Honoraria Astra Zeneca Australia, Roche Diagnostic. Unrestricted Grant:

Edwards Life Sciences, Roche Diagnostic (this study)

KL: None

AB: None

AS: None

MJRE: None

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TB: None

LAC: Research grants: Abbott Diagnostics, Siemens, Beckman Coulter. Speaker Honoraria

Siemens, Abbott Diagnostics, Novartis, Astra Zeneca.

SQ: None

JK:None

AC: None

AJN: None

DW: None

MH: None

EM: None

JKF: None

CP: None

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Table 1. Baseline Characteristics of all study particpants (intention to treat population)

Characteristic

Standard Protocol

(N=1642)

0/1-Hour Protocol

(N=1646)

Age (median, IQR) 58.6 (48.8, 71.2) 58.7 (48.6, 69.4)

Female sex -no. (%) 768/1642 (46.8) 771/1646 (46.8)

Hypertension -no. (%) 337/1642 (20.5) 324/1646 (19.7)

Diabetes -no. (%) 286/1642 (17.4) 260/1646 (15.8)

Dyslipidaemia-no. (%) 723/1642 (44.0) 712/1646 (43.3)

Current smoker -no. (%) 584/1642 (35.6) 570/1646 (34.6)

Family history of CAD -no. (%) 953/1612 (59.1) 992/1620 (61.2)

Prior history of CAD -no. (%) 477/1642 (29.0) 457/1646 (27.8)

Prior myocardial infarction -no. (%) 161/1642 (9.8) 170/1646 (10.3)

Prior angina -no. (%) 260/1642 (15.8) 250/1646 (15.2)

Prior heart hailure -no. (%) 93/1642 (5.7) 78/1646 (4.7)

Prior atrial fibrillation -no. (%) 154/1642 (9.4) 135/1646 (8.2)

Chronic obstructive airways disease -no. (%) 74/1642 (4.5) 77/1646 (4.7)

Prior cerebrovascular disease -no. (%) 52/1642 (3.2) 53/1646 (3.2)

Prior coronary artery bypass grafting -no. (%) 46/1642 (2.8%) 49/1646 (3.0%)

Prior percutaneous coronary intervention -no. (%) 138/1642 (8.4%) 171/1646 (10.4%)

Systolic blood pressure (mmHg, median, IQR)* 135 (122,151) 135 (121, 150)

Heart rate (bpm, median, IQR) 75 (66, 85) 74 (65, 85)

Killip class Class 1 1591/1642 (96.9%) 1614/1646 (98.1%)

Class 2 48/1642 (2.9%) 27/1646 (1.6%)

Class 3 3/1642 (0.2%) 5/1646 (0.3%)

Weight (kg, median, IQR) 82 (70, 96) 83 (71, 96)

Height (cm, median, IQR) 170 (160, 178) 170 (160, 178)

Body mass index, (kg/m2, median, IQR) † 28.3 (24.8, 32.9) 28.7 (25.3, 32.9)

Glomerular filtration rate (ml/min/1.73m2, median,IQR) * ‡ 86.0 (71.1, 98.1) 86.2 (71.6, 98.2)

EDACS, median (IQR) 15.0 (9.0, 21.0) 14.0 (9.0, 20.0)

GRACE score, median (IQR)* 75.0 (56.1, 100.8) 74.1 (55.2, 97.2)

TIMI NSTEACS score, median (IQR) 1.0 (0.0, 3.0) 1.0 (0.0, 2.0)

HEART score, median (IQR) 3.0 (2.0, 4.0) 3.0 (2.0, 4.0)

Footnote:

Abbreviations: IQR: inter quartile range, CAD: coronary artery disease, EDACS: Emergency Department

Assessment of Chest Pain Score, HEART: History ECG Age Risk factors and Troponin, GRACE: Global Registry

for Acute Coronary Events, TIMI: Thrombolysis In Myocardial Infarction, NSTEACS: non ST-segment elevation

acute coronary syndrome, CKD: chronic kidney disease

There were no significant differences (P


30

Table 2. Performance of Troponin Testing, Index Admission Classification, and Subsequent cardiac

testing and revascularization in the ITT population and participants with initial troponin ≤29ng/L.

Clinical Care Characteristic

Standard Protocol

(N=1642)

0/1-Hour Protocol

(N=1646) p-value

All participants

Time between troponin testing, (hours, median (IQR) 3.1 (2.9, 3.5) 1.0 (1.0, 1.2) 30ng/L in first 12 hours, no. (%) 140/1632 (8.6%) 142/1644 (8.6%) 0.95

ED working diagnosis

Non-cardiac diagnosis, no. (%) 135/1642 (8.2%) 153/1646 (9.3%) 0.620

Chest pain, no. (%) 1017/1642 (61.9%) 997/1646 (60.6%)

Other cardiac diagnosis, no. (%) 425/1642 (25.9%) 437/1646 (26.6%)

Myocardial Infarction , no. (%) 65/1642 (4.0%) 59/1646 (3.6%)

Discharged from ED, no. (%) 531/1642 (32.3%) 742/1646 (45.1%)


31

Acute Care length of stay, hrs, median (IQR) 6.3/1493 (4.8, 18.4) 5.1/1515 (3.6, 18.2)


32

Table 3. Primary and Secondary Outcomes in the overall ITT population and those with an initial troponin ≤29 ng/L

Standard

Protocol

(N=1642)

0/1-Hour

Protocol

(N=1646)

IRR

(95% C.I.) p-

value

Non-

inferiority

p-value ‡

Outcome

number of patients

(percent)

All participants

Primary Endpoint: death or myocardial infarction within 30 days 16 (1.0%) 17 (1.0%) 1.06 (0.53-2.11) 0.867

0.006

All-cause death 6 (0.4%) 2 (0.1%) 0.33 (0.03-3.43) 0.355

Cardiovascular death 3 (0.2%) 2 (0.1%) 0.67 (0.10-4.25) 0.667

Myocardial Infarction (Type 1, Type2, Type 4a, Type 5)* 10 (0.6%) 15 (0.9%) 1.50 (0.81-2.78) 0.197

acute myocardial injury with/without revascularization* 7 (0.4%) 11 (0.7%) 1.57 (1.31-1.88)


33

Table 4. Primary and Secondary Endpoint at 30 days by triage category for participants (Intention to treat

population)

Standard Protocol 0/1-Hour Protocol

Outcome cTnT29ng/L

(N=1493)

cTnT>29ng/L

(N=140) MI Rule out

(N=1,187)

MI Observe

(N=308)

MI Rule In

(N=136)

Primary Endpoint: death and myocardial infarction 9 (0.6%) 7 (5.0%) 5 (0.4%) 7 (2.3%) 5 (3.7%)

All-cause death 2 (0.1%) 4 (2.9%) 1 (0.1%) 1 (0.3%) 0 (0.0%)

Cardiovascular death 0 (0.0%) 3 (2.1%) 1 (0.1%) 1 (0.3%) 0 (0.0%)

Myocardial infarction

(Type 1, Type 2, Type 4a, Type 5)* 7 (0.5%) 3 (2.1%) 4 (0.3%) 6 (1.9%) 5 (3.7%)

Myocardial injury – acute* 6 (0.4%) 1 (0.7%) 5 (0.4%) 3 (1.0%) 3 (2.2%)

Myocardial infarction and myocardial injury – acute* 13 (0.9%) 4 (2.9%) 9 (0.8%) 9 (2.9%) 8 (5.9%)

Myocardial injury – chronic* 13 (0.9%) 8 (5.7%) 2 (0.2%) 11 (3.6%) 5 (3.7%)

Unstable angina 4 (0.3%) 0 (0.0%) 3 (0.3%) 2 (0.6%) 0 (0.0%)

All-cause death and myocardial infarction and

unstable angina 11 (0.7%) 6 (4.3%) 7 (0.6%) 9 (2.9%) 5 (3.7%)

Chest pain representation 39 (2.6%) 5 (3.6%) 41 (3.5%) 22 (7.1%) 7 (5.1%)

Cardiovascular rehospitalisation† 10 (0.7%) 5 (3.6%) 9 (0.8%) 8 (2.6%) 6 (4.4%)

BARC 2, 3a, or 4 4 (0.3%) 9 (6.4%) 2 (0.2%) 2 (0.6%) 2 (1.5%)

TIMI major, minor or minimal 3 (0.2%) 6 (4.3%) 1 (0.1%) 2 (0.6%) 1 (0.7%)

GUSTO major or minor 1 (0.1%) 6 (4.3%) 1 (0.1%) 1 (0.3%) 2 (1.5%)

Footnote:

Abbreviations: BARC: Bleeding Academic Research Consortium, TIMI: Thrombolysis In Myocardial, GUSTO: Global Utilization of Strategies

to open Occluded arteries.

*All troponin T results >14ng/L adjudicated according to the Fourth Universal Definition of Myocardial Infarction. A rise and/or fall pattern

required a change troponin concentration of >20% and a rate of change arbitrarily defined as ≥3ng/L/hr. 22,23 †Cardiovascular rehospitalization includes readmission for non-elective coronary revascularization, peripheral artery disease, cerebrovascular

accidents; congestive cardiac failure without MI, atrial and ventricular arrhythmias.

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Figure Legends

Figure 1. Screening, Eligibility, Randomization and Follow-up

Figure 2. Measures of Clinical Care. Odds ratio for likelihood of functional cardiac testing,

coronary angiography and coronary revascularization stratified by peak troponin concentration

within initial assessment. NB: peak concentrations ≤29ng/L not observed by clinicians

randomized to the standard therapy arm.

Figure 3. Clinical Outcomes within 30 days. Kaplan Meier Event Curves for (a) the primary

endpoint within 30 days, and (b) cardiovascular rehospitalization within 30 days. Cardiovascular

rehospitalization includes readmission for non-elective coronary revascularization, peripheral

artery disease, cerebrovascular accidents; congestive cardiac failure without MI, atrial and

ventricular arrhythmias.

Footnote: Standard: Masked hs-cTnT protocol; 0/1-Hour: 0/1-Hour hs-cTnT protocol

Dow


ber 5, 2019

Dow


ber 5, 2019

A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected … · 2019. 10. 10. ·...

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